PROJECT SUMMARY/ABSTRACT HIV-1 infection causing an incurable disease resulting in chronic inflammation that leads to comorbidities. Recent evidence has suggested an important role of purinergic receptors and downstream inflammasome signaling mediators and important contributors to HIV-1 entry and in driving inflammation. Preliminary data indicate that inhibitors of purinergic signaling reduce both HIV-1 infection and inflammatory cytokine signaling. Our goal is to elucidate the role of HIV-1 in mediating inflammatory signaling in lymphoid tissue. This study is the proposal of an early stage investigator physician scientist who will bring together expertise in HIV virology, immunology, and genomics to test the following aims: 1) Differentiating the inflammatory and stromal cell types required for HIV-associated inflammatory signaling in peripheral blood, dissociated tonsils and tonsil blocks. 2) Differentiating patterns of infected and bystander cells through correlative imaging and transcriptomic analysis of infected tonsil blocks. The methods proposed are novel in that they utilize a recently developed ex vivo human tonsil infection model and a single cell imaging and gene expression platform that will allow for understanding the inflammatory signaling that is associated with HIV-1 infection on a single cell level. The investigators and collaborators offer complimentary expertise and the facilities at the Mount Sinai Health System are uniquely capable of supporting these studies with core facilities, large patient cohorts, and institutional support. The Icahn School of Medicine at Mount Sinai has demonstrated commitment to the career development of this early stage principal investigator. The goal is to develop a successful career of the PI as an independent physician scientist in dissecting out the pathogenesis of the HIV-1 infection and downstream signaling in HIV-1 infection with the goal of finding key therapeutic agents in the treatment of HIV-1 infection and inflammation and in understanding and reversing HIV-1 latency in the development of a cure.